5,5-Dimethyl-3-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) -1-phenyl-3-(trifluoromethyl)-3,5,6,7-tetrahydro-1H-indole-2,4-dione, a potent inhibitor for mammalian elongase of long-chain fatty acids family 6

Examination of its potential utility as a pharmacological tool

Ken Shimamura, Hidefumi Kitazawa, Yasuhisa Miyamoto, Maki Kanesaka, Akira Nagumo, Ryo Yoshimoto, Katsumi Aragane, Naomi Morita, Tomoyuki Ohe, Toshiyuki Takahashi, Tsuyoshi Nagase, Nagaaki Sato, Shigeru Tokita

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Long-chain fatty acid elongases reside in the endoplasmic reticulum and are responsible for the rate-limiting step of the elongation of long-chain fatty acids. The elongase of long-chain fatty acids (ELOVL) family 6 (ELOVL6) is involved in the elongation of saturated and monosaturated fatty acids. Increased expression of ELOVL6 in ob/ob mice suggests a role for ELOVL6 in metabolic disorders. Furthermore, ELOVL6-deficient mice are protected from high-fat diet-induced insulin resistance, which suggests that ELOVL6 might be a new therapeutic target for diabetes. As reported previously, we developed a high-throughput screening system for fatty acid elongases and discovered lead chemicals that possess inhibitory activities against ELOVL6. In the present study, we examined in detail the biochemical and pharmacological properties of 5,5-dimethyl-3-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1Hpyrazol-4-yl) -1-phenyl-3-(trifluoromethyl)-3,5,6,7-tetrahydro-1H-indole-2,4-dione (Compound-A), a potent inhibitor of ELOVL6. In in vitro assays, Compound-A dose-dependently inhibited mouse and human ELOVL6 and displayed more than 30-fold greater selectivity for ELOVL6 over the other ELOVL family members. In addition, Compound-A effectively reduced the elongation index of fatty acids of hepatocytes, suggesting that Compound-A penetrates the cell wall and inhibits ELOVL6. More importantly, upon oral administration to mice, Compound-A showed high plasma and liver exposure and potently reduced the elongation index of the fatty acids of the liver. This is the first study to report a potent and selective inhibitor of mammalian elongases. Furthermore, Compound-A seems to be a useful tool to further understand the physiological roles of ELOVL6 and to evaluate the therapeutic potential of an ELOVL6 inhibitor.

Original languageEnglish
Pages (from-to)249-256
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume330
Issue number1
DOIs
Publication statusPublished - 2009 Jul
Externally publishedYes

Fingerprint

Fatty Acids
Pharmacology
5,5-dimethyl-3-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-)-1-phenyl-3-(trifluoromethyl)-3,5,6,7-tetrahydro-1H-indole-2,4-dione
High Fat Diet
Fatty Liver
Endoplasmic Reticulum
Cell Wall
Oral Administration
Insulin Resistance
Hepatocytes
Liver
Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

5,5-Dimethyl-3-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) -1-phenyl-3-(trifluoromethyl)-3,5,6,7-tetrahydro-1H-indole-2,4-dione, a potent inhibitor for mammalian elongase of long-chain fatty acids family 6 : Examination of its potential utility as a pharmacological tool. / Shimamura, Ken; Kitazawa, Hidefumi; Miyamoto, Yasuhisa; Kanesaka, Maki; Nagumo, Akira; Yoshimoto, Ryo; Aragane, Katsumi; Morita, Naomi; Ohe, Tomoyuki; Takahashi, Toshiyuki; Nagase, Tsuyoshi; Sato, Nagaaki; Tokita, Shigeru.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 330, No. 1, 07.2009, p. 249-256.

Research output: Contribution to journalArticle

Shimamura, Ken ; Kitazawa, Hidefumi ; Miyamoto, Yasuhisa ; Kanesaka, Maki ; Nagumo, Akira ; Yoshimoto, Ryo ; Aragane, Katsumi ; Morita, Naomi ; Ohe, Tomoyuki ; Takahashi, Toshiyuki ; Nagase, Tsuyoshi ; Sato, Nagaaki ; Tokita, Shigeru. / 5,5-Dimethyl-3-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) -1-phenyl-3-(trifluoromethyl)-3,5,6,7-tetrahydro-1H-indole-2,4-dione, a potent inhibitor for mammalian elongase of long-chain fatty acids family 6 : Examination of its potential utility as a pharmacological tool. In: Journal of Pharmacology and Experimental Therapeutics. 2009 ; Vol. 330, No. 1. pp. 249-256.
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